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Concise Chemoenzymatic Three Step Total Synthesis of Isosolenopsin Through Medium Engineering.

Simon RC, Fuchs CS, Lechner H, Zepeck F, Kroutil W - European J Org Chem (2013)

Bottom Line: A short and efficient total synthesis of the alkaloid isosolenopsin and its enantiomer has been achieved.Diastereostelective chemical reduction (H2/Pd/C) of the biocatalytic product gave the target compound.The linear three step synthesis provided the natural product isosolenopsin in diastereomerically pure form (ee > 99%, d.r. = 99:1) with an overall yield of 64%.

View Article: PubMed Central - PubMed

Affiliation: ACIB GmbH, Heinrichstraße 28, 8010-Graz, Austria.

ABSTRACT
A short and efficient total synthesis of the alkaloid isosolenopsin and its enantiomer has been achieved. In the key step, a ω-transaminase catalyzed the regioselective mono-amination of the diketone pentadecane-2,6-dione which was obtained in a single step via Grignard reaction. Initial low conversions in the biotransformation could be overcome by optimisation of the reaction conditions employing suitable cosolvents. In the presence of 20 vol% DMF or n-heptane best results were obtained employing two enantio-complementary ω-transaminases originating from Arthrobacter between 30-40 °C; under these conditions conversions of >99% and perfect stereocontrol (ee > 99%) were achieved. Diastereostelective chemical reduction (H2/Pd/C) of the biocatalytic product gave the target compound. The linear three step synthesis provided the natural product isosolenopsin in diastereomerically pure form (ee > 99%, d.r. = 99:1) with an overall yield of 64%.

No MeSH data available.


Related in: MedlinePlus

Chemoenzymatic synthesis of both enantiomers of isosolenopsins (2S,6R)-1a and (2R,6S)-1a under the optimised reaction conditions. Reagents and conditions: (a) Diketone 3a (36 mg, 0.15 mmol, 25 mm) dissolved in DMF (20 vol.-%), ω-TA from Arthrobacter citreus, PLP (1 mm), NAD+ (1 mm), L-alanine (20 equiv.), ammonium formate (150 mm), 11 U FDH, 12 U AlaDH, 48 h, 40 °C, 700 rpm; (b) same as for (a) but with the ω-TA from (R)-Arthrobacter sp. at 30 °C with D-alanine and 20 vol.-% n-heptane, 5 vol.-% DMF; (c) Pd/C, H2 (1 atm.), 4 h, 22 °C; precipitation with etherial HCl solution (5 equiv.).
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fig08: Chemoenzymatic synthesis of both enantiomers of isosolenopsins (2S,6R)-1a and (2R,6S)-1a under the optimised reaction conditions. Reagents and conditions: (a) Diketone 3a (36 mg, 0.15 mmol, 25 mm) dissolved in DMF (20 vol.-%), ω-TA from Arthrobacter citreus, PLP (1 mm), NAD+ (1 mm), L-alanine (20 equiv.), ammonium formate (150 mm), 11 U FDH, 12 U AlaDH, 48 h, 40 °C, 700 rpm; (b) same as for (a) but with the ω-TA from (R)-Arthrobacter sp. at 30 °C with D-alanine and 20 vol.-% n-heptane, 5 vol.-% DMF; (c) Pd/C, H2 (1 atm.), 4 h, 22 °C; precipitation with etherial HCl solution (5 equiv.).

Mentions: The synthetic potential was finally demonstrated in the total synthesis of both enantiomers of isosolenopsin [(2S,6R)-1a and (2R,6S)-1a]. Starting with a Grignard reaction, the required diketone 3a was obtained in a single step from commercially available dihydropyrane-2-one 9 in 65 % yield (Scheme 3). The subsequent biotransformation was conducted under the optimised conditions on an increased scale (36 mg, 0.15 mmol, 25 mm); the ω-TA of Arthrobacter sp. gave access to the (R)-enantiomer, whereas the ω-TA of Arthrobacter citreus gave the (S)-enantiomer of piperidine 6a. Both reactions yielded the corresponding cyclic imine (R)- and (S)-6a, respectively, in optically pure form (ee > 99 %) at full conversion (> 99 % in both cases). Notably, the reaction times were prolonged (48 h) to ensure full conversion and hence simplify the work up procedures. Due to the instability of imine 6a, it was directly subjected to diastereoselective reduction using hydrogen with Pd/C as catalyst after extraction. Under these conditions, the second stereocentre was established under perfect substrate control, affording the natural product (2S,6R)-1a and (2S,6R)-1a in diastereomerically pure form [dr (syn/anti) = 99 % as deduced by GC and NMR analysis] in an excellent yield of 94–98 % (over two steps). Thus, starting from pyranone 9, the natural alkaloids (+)-1a and (–)-1a were obtained in optically pure form in 64 % overall yield.


Concise Chemoenzymatic Three Step Total Synthesis of Isosolenopsin Through Medium Engineering.

Simon RC, Fuchs CS, Lechner H, Zepeck F, Kroutil W - European J Org Chem (2013)

Chemoenzymatic synthesis of both enantiomers of isosolenopsins (2S,6R)-1a and (2R,6S)-1a under the optimised reaction conditions. Reagents and conditions: (a) Diketone 3a (36 mg, 0.15 mmol, 25 mm) dissolved in DMF (20 vol.-%), ω-TA from Arthrobacter citreus, PLP (1 mm), NAD+ (1 mm), L-alanine (20 equiv.), ammonium formate (150 mm), 11 U FDH, 12 U AlaDH, 48 h, 40 °C, 700 rpm; (b) same as for (a) but with the ω-TA from (R)-Arthrobacter sp. at 30 °C with D-alanine and 20 vol.-% n-heptane, 5 vol.-% DMF; (c) Pd/C, H2 (1 atm.), 4 h, 22 °C; precipitation with etherial HCl solution (5 equiv.).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4151137&req=5

fig08: Chemoenzymatic synthesis of both enantiomers of isosolenopsins (2S,6R)-1a and (2R,6S)-1a under the optimised reaction conditions. Reagents and conditions: (a) Diketone 3a (36 mg, 0.15 mmol, 25 mm) dissolved in DMF (20 vol.-%), ω-TA from Arthrobacter citreus, PLP (1 mm), NAD+ (1 mm), L-alanine (20 equiv.), ammonium formate (150 mm), 11 U FDH, 12 U AlaDH, 48 h, 40 °C, 700 rpm; (b) same as for (a) but with the ω-TA from (R)-Arthrobacter sp. at 30 °C with D-alanine and 20 vol.-% n-heptane, 5 vol.-% DMF; (c) Pd/C, H2 (1 atm.), 4 h, 22 °C; precipitation with etherial HCl solution (5 equiv.).
Mentions: The synthetic potential was finally demonstrated in the total synthesis of both enantiomers of isosolenopsin [(2S,6R)-1a and (2R,6S)-1a]. Starting with a Grignard reaction, the required diketone 3a was obtained in a single step from commercially available dihydropyrane-2-one 9 in 65 % yield (Scheme 3). The subsequent biotransformation was conducted under the optimised conditions on an increased scale (36 mg, 0.15 mmol, 25 mm); the ω-TA of Arthrobacter sp. gave access to the (R)-enantiomer, whereas the ω-TA of Arthrobacter citreus gave the (S)-enantiomer of piperidine 6a. Both reactions yielded the corresponding cyclic imine (R)- and (S)-6a, respectively, in optically pure form (ee > 99 %) at full conversion (> 99 % in both cases). Notably, the reaction times were prolonged (48 h) to ensure full conversion and hence simplify the work up procedures. Due to the instability of imine 6a, it was directly subjected to diastereoselective reduction using hydrogen with Pd/C as catalyst after extraction. Under these conditions, the second stereocentre was established under perfect substrate control, affording the natural product (2S,6R)-1a and (2S,6R)-1a in diastereomerically pure form [dr (syn/anti) = 99 % as deduced by GC and NMR analysis] in an excellent yield of 94–98 % (over two steps). Thus, starting from pyranone 9, the natural alkaloids (+)-1a and (–)-1a were obtained in optically pure form in 64 % overall yield.

Bottom Line: A short and efficient total synthesis of the alkaloid isosolenopsin and its enantiomer has been achieved.Diastereostelective chemical reduction (H2/Pd/C) of the biocatalytic product gave the target compound.The linear three step synthesis provided the natural product isosolenopsin in diastereomerically pure form (ee > 99%, d.r. = 99:1) with an overall yield of 64%.

View Article: PubMed Central - PubMed

Affiliation: ACIB GmbH, Heinrichstraße 28, 8010-Graz, Austria.

ABSTRACT
A short and efficient total synthesis of the alkaloid isosolenopsin and its enantiomer has been achieved. In the key step, a ω-transaminase catalyzed the regioselective mono-amination of the diketone pentadecane-2,6-dione which was obtained in a single step via Grignard reaction. Initial low conversions in the biotransformation could be overcome by optimisation of the reaction conditions employing suitable cosolvents. In the presence of 20 vol% DMF or n-heptane best results were obtained employing two enantio-complementary ω-transaminases originating from Arthrobacter between 30-40 °C; under these conditions conversions of >99% and perfect stereocontrol (ee > 99%) were achieved. Diastereostelective chemical reduction (H2/Pd/C) of the biocatalytic product gave the target compound. The linear three step synthesis provided the natural product isosolenopsin in diastereomerically pure form (ee > 99%, d.r. = 99:1) with an overall yield of 64%.

No MeSH data available.


Related in: MedlinePlus